Modelling the health and economic impacts ofM72/AS01E vaccination and BCG-revaccination: Estimates for South Africa.

BACKGROUND: Tuberculosis remains a major public health problem in South Africa, with an estimated 300,000 cases and 55,000 deaths in 2021. New tuberculosis vaccines could play an important role in reducing this burden. Phase IIb trials have suggested efficacy of the M72/AS01E vaccine candidate and BCG-revaccination. The potential population impact of these vaccines is unknown. METHODS: We used an age-stratified transmission model of tuberculosis, calibrated to epidemiological data from South Africa, to estimate the potential health and economic impact of M72/AS01E vaccination and BCG-revaccination. We simulated M72/AS01E vaccination scenarios over the period 2030-2050 and BCG-revaccination scenarios over the period 2025-2050. We explored a range of product characteristics and delivery strategies. We calculated reductions in tuberculosis cases and deaths and costs and cost-effectiveness from health-system and societal perspectives. FINDINGS: M72/AS01E vaccination may have a larger impact than BCG-revaccination, averting approximately 80% more cases and deaths by 2050. Both vaccines were found to be cost-effective or cost saving (compared to no new vaccine) across a range of vaccine characteristics and delivery strategies from both the health system and societal perspective. The impact of M72/AS01E is dependent on the assumed efficacy of the vaccine in uninfected individuals. Extending BCG-revaccination to HIV-infected individuals on ART increased health impact by approximately 15%, but increased health system costs by approximately 70%. INTERPRETATION: Our results show that M72/AS01E vaccination or BCG-revaccination could be cost-effective in South Africa. However, there is considerable uncertainty in the estimated impact and costs due to uncertainty in vaccine characteristics and the choice of delivery strategy. FUNDING: This work was funded by the Bill & Melinda Gates Foundation (INV-001754). This work used the Cirrus UK National Tier-2 HPC Service at EPCC (https://www.cirrus.ac.uk) funded by the University of Edinburgh and EPSRC (EP/P020267/1).

The potential health and economic impacts of new tuberculosis vaccines under varying delivery strategies in Delhi and Gujarat, India: a modelling study.

Background: India has the largest tuberculosis burden globally, but this burden varies nationwide. All-age tuberculosis prevalence in 2021 ranged from 747/100,000 in Delhi to 137/100,000 in Gujarat. Previous modelling has demonstrated the benefits and costs of introducing novel tuberculosis vaccines in India overall. However, no studies have compared the potential impact of tuberculosis vaccines in regions within India with differing tuberculosis disease and infection prevalence. We used mathematical modelling to investigate how the health and economic impact of two potential tuberculosis vaccines, M72/AS01E and BCG-revaccination, could differ in Delhi and Gujarat under varying delivery strategies. Methods: We applied a compartmental tuberculosis model separately for Delhi (higher disease and infection prevalence) and Gujarat (lower disease and infection prevalence), and projected epidemiological trends to 2050 assuming no new vaccine introduction. We simulated M72/AS01E and BCG-revaccination scenarios varying target ages and vaccine characteristics. We estimated cumulative cases, deaths, and disability-adjusted life years averted between 2025-2050 compared to the no-new-vaccine scenario and compared incremental cost-effectiveness ratios to three cost-effectiveness thresholds. Results: M72/AS01E averted a higher proportion of tuberculosis cases than BCG-revaccination in both regions (Delhi: 16.0% vs 8.3%, Gujarat: 8.5% vs 5.1%) and had higher vaccination costs (Delhi: USD$118 million vs USD$27 million, Gujarat: US$366 million vs US$97 million). M72/AS01E in Delhi could be cost-effective, or even cost-saving, for all modelled vaccine characteristics. M72/AS01E could be cost-effective in Gujarat, unless efficacy was assumed only for those with current infection at vaccination. BCG-revaccination could be cost-effective, or cost-saving, in both regions for all modelled vaccine scenarios. Discussion: M72/AS01E and BCG-revaccination could be impactful and cost-effective in Delhi and Gujarat. Differences in impact, costs, and cost-effectiveness between vaccines and regions, were determined partly by differences in disease and infection prevalence, and demography. Age-specific regional estimates of infection prevalence could help to inform delivery strategies for vaccines that may only be effective in people with a particular infection status. Evidence on the mechanism of effect of M72/AS01E and its effectiveness in uninfected individuals, which were important drivers of impact and cost-effectiveness, particularly in Gujarat, are also key to improve estimates of population-level impact.

Cost-effectiveness of routine adolescent vaccination with an M72/AS01E-like tuberculosis vaccine in South Africa and India.

The M72/AS01E tuberculosis vaccine showed 50% (95%CI: 2-74%) efficacy in a phase 2B trial in preventing active pulmonary tuberculosis disease, but potential cost-effectiveness of adolescent immunisation is unknown. We estimated the impact and cost-effectiveness of six scenarios of routine adolescent M72/AS01E-like vaccination in South Africa and India. All scenarios suggested an M72/AS01E-like vaccine would be highly (94-100%) cost-effective in South Africa compared to a cost-effectiveness threshold of $2480/disability-adjusted life-year (DALY) averted. For India, a prevention of disease vaccine, effective irrespective of recipient's M. tuberculosis infection status at time of administration, was also highly likely (92-100%) cost-effective at a threshold of $264/DALY averted; however, a prevention of disease vaccine, effective only if the recipient was already infected, had 0-6% probability of cost-effectiveness. In both settings, vaccinating 50% of 18 year-olds was similarly cost-effective to vaccinating 80% of 15 year-olds, and more cost-effective than vaccinating 80% of 10 year-olds. Vaccine trials should include adolescents to ensure vaccines can be delivered to this efficient-to-target population.

Population benefits of addressing programmatic and social determinants of gender disparities in tuberculosis in Viet Nam: A modelling study.

High prevalence of infectious tuberculosis among men suggests potential population-wide benefits from addressing programmatic and social determinants of gender disparities. Utilising a sex-stratified compartmental transmission model calibrated to tuberculosis burden estimates for Viet Nam, we modelled interventions to increase active case finding, to reduce tobacco smoking, and to reduce alcohol consumption by 2025 in line with national and global targets. For each intervention, we examined scenarios differentially targeting men and women and evaluated impact on tuberculosis morbidity and mortality in men, women, and children in 2035. Active case finding interventions targeting men projected greater reductions in tuberculosis incidence in men, women, and children (16.2%, uncertainty interval, UI, 11.4-23.0%, 11.8%, UI 8.0-18.6%, and 21.5%, UI 16.9-28.5%, respectively) than those targeting women (5.2%, UI 3.8-7.1%, 5.4%, UI 3.9-7.3%, and 8.6%, UI 6.9-10.7%, respectively). Projected reductions in tuberculosis incidence for interventions to reduce male tobacco smoking and alcohol consumption were greatest for men (17.4%, UI 11.8-24.7%, and 11.0%, UI 5.4-19.4%, respectively), but still substantial for women (6.9%, UI 3.8-12.5%, and 4.4%, UI 1.9-10.6%, respectively) and children (12.7%, UI 8.4-19.0%, and 8.0%, UI 3.9-15.0%, respectively). Comparable interventions targeting women projected limited impact, with declines of 0.3% (UI 0.2%-0.3%) and 0.1% (UI 0.0%-0.1%), respectively. Addressing programmatic and social determinants of men's tuberculosis burden has population-wide benefits. Future interventions to increase active case finding, to reduce tobacco smoking, and to reduce harmful alcohol consumption, whilst not ignoring women, should focus on men to most effectively reduce tuberculosis morbidity and mortality in men, women, and children.

Informing Balanced Investment in Services and Health Systems: A Case Study of Priority Setting for Tuberculosis Interventions in South Africa.

OBJECTIVES: Health systems face nonfinancial constraints that can influence the opportunity cost of interventions. Empirical methods to explore their impact, however, are underdeveloped. We develop a conceptual framework for defining health system constraints and empirical estimation methods that rely on routine data. We then present an empirical approach for incorporating nonfinancial constraints in cost-effectiveness models of health benefit packages for the health sector. METHODS: We illustrate the application of this approach through a case study of defining a package of services for tuberculosis case-finding in South Africa. An economic model combining transmission model outputs with unit costs was developed to examine the cost-effectiveness of alternative screening and diagnostic algorithms. Constraints were operationalized as restrictions on achievable coverage based on: (1) financial resources; (2) human resources; and (3) policy constraints around diagnostics purchasing. Cost-effectiveness of the interventions was assessed under one "unconstrained" and several "constrained" scenarios. For the unconstrained scenario, incremental cost-effectiveness ratios were estimated with and without the costs of "relaxing" constraints. RESULTS: We find substantial differences in incremental cost-effectiveness ratios across scenarios, leading to variations in the decision rules for prioritizing interventions. In constrained scenarios, the limiting factor for most interventions was not financial, but rather the availability of human resources. CONCLUSIONS: We find that optimal prioritization among different tuberculosis control strategies in South Africa is influenced by whether and how constraints are taken into consideration. We thus demonstrate both the importance and feasibility of considering nonfinancial constraints in health sector resource allocation models.

Should NICE reconsider the 2016 UK guidelines on TB contact tracing? A cost-effectiveness analysis of contact investigations in London.

BACKGROUND: In January 2016, clinical TB guidance in the UK changed to no longer recommend screening contacts of non-pulmonary, non-laryngeal (ETB) index cases. However, no new evidence was cited for this change, and there is evidence that screening these contacts may be worthwhile. The objective of this study was to estimate the cost-effectiveness of screening contacts of adult ETB cases and adult pulmonary or laryngeal TB (PTB) cases in London, UK. METHODS: We carried out a cross-sectional analysis of data collected on TB index cases and contacts in the London TB register and an economic evaluation using a static model describing contact tracing outcomes. Incremental cost-effectiveness ratios (ICERs) were calculated using no screening as the baseline comparator. All adult TB cases (≥15 years old) in London from 2012 to 2015, and their contacts, were eligible (2465/5084 PTB and 2559/6090 ETB index cases were included). RESULTS: Assuming each contact with PTB infects one person/month, the ICER of screening contacts of ETB cases was £78 000/quality-adjusted life-years (QALY) (95% CI 39 000 to 140 000), and screening contacts of PTB cases was £30 000/QALY (95% CI 18 000 to 50 000). The ICER of screening contacts of ETB cases was £30 000/QALY if each contact with PTB infects 3.4 people/month. Limitations of this study include the use of self-reported symptomatic periods and lack of knowledge about onward transmission from PTB contacts. CONCLUSIONS: Screening contacts of ETB cases in London was almost certainly not cost-effective at any conventional willingness-to-pay threshold in England, supporting recent changes to National Institute for Health and Care Excellence national guidelines.

Empirical estimation of resource constraints for use in model-based economic evaluation: an example of TB services in South Africa.

BACKGROUND: Evidence on the relative costs and effects of interventions that do not consider 'real-world' constraints on implementation may be misleading. However, in many low- and middle-income countries, time and data scarcity mean that incorporating health system constraints in priority setting can be challenging. METHODS: We developed a 'proof of concept' method to empirically estimate health system constraints for inclusion in model-based economic evaluations, using intensified case-finding strategies (ICF) for tuberculosis (TB) in South Africa as an example. As part of a strategic planning process, we quantified the resources (fiscal and human) needed to scale up different ICF strategies (cough triage and WHO symptom screening). We identified and characterised three constraints through discussions with local stakeholders: (1) financial constraint: potential maximum increase in public TB financing available for new TB interventions; (2) human resource constraint: maximum current and future capacity among public sector nurses that could be dedicated to TB services; and (3) diagnostic supplies constraint: maximum ratio of Xpert MTB/RIF tests to TB notifications. We assessed the impact of these constraints on the costs of different ICF strategies. RESULTS: It would not be possible to reach the target coverage of ICF (as defined by policy makers) without addressing financial, human resource and diagnostic supplies constraints. The costs of addressing human resource constraints is substantial, increasing total TB programme costs during the period 2016-2035 by between 7% and 37% compared to assuming the expansion of ICF is unconstrained, depending on the ICF strategy chosen. CONCLUSIONS: Failure to include the costs of relaxing constraints may provide misleading estimates of costs, and therefore cost-effectiveness. In turn, these could impact the local relevance and credibility of analyses, thereby increasing the risk of sub-optimal investments.

Catastrophic costs potentially averted by tuberculosis control in India and South Africa: a modelling study.

BACKGROUND: The economic burden on households affected by tuberculosis through costs to patients can be catastrophic. WHO's End TB Strategy recognises and aims to eliminate these potentially devastating economic effects. We assessed whether aggressive expansion of tuberculosis services might reduce catastrophic costs. METHODS: We estimated the reduction in tuberculosis-related catastrophic costs with an aggressive expansion of tuberculosis services in India and South Africa from 2016 to 2035, in line with the End TB Strategy. Using modelled incidence and mortality for tuberculosis and patient-incurred cost estimates, we investigated three intervention scenarios: improved treatment of drug-sensitive tuberculosis; improved treatment of multidrug-resistant tuberculosis; and expansion of access to tuberculosis care through intensified case finding (South Africa only). We defined tuberculosis-related catastrophic costs as the sum of direct medical, direct non-medical, and indirect costs to patients exceeding 20% of total annual household income. Intervention effects were quantified as changes in the number of households incurring catastrophic costs and were assessed by quintiles of household income. FINDINGS: In India and South Africa, improvements in treatment for drug-sensitive and multidrug-resistant tuberculosis could reduce the number of households incurring tuberculosis-related catastrophic costs by 6-19%. The benefits would be greatest for the poorest households. In South Africa, expanded access to care could decrease household tuberculosis-related catastrophic costs by 5-20%, but gains would be seen largely after 5-10 years. INTERPRETATION: Aggressive expansion of tuberculosis services in India and South Africa could lessen, although not eliminate, the catastrophic financial burden on affected households. FUNDING: Bill & Melinda Gates Foundation.

Cost-effectiveness and resource implications of aggressive action on tuberculosis in China, India, and South Africa: a combined analysis of nine models.

BACKGROUND: The post-2015 End TB Strategy sets global targets of reducing tuberculosis incidence by 50% and mortality by 75% by 2025. We aimed to assess resource requirements and cost-effectiveness of strategies to achieve these targets in China, India, and South Africa. METHODS: We examined intervention scenarios developed in consultation with country stakeholders, which scaled up existing interventions to high but feasible coverage by 2025. Nine independent modelling groups collaborated to estimate policy outcomes, and we estimated the cost of each scenario by synthesising service use estimates, empirical cost data, and expert opinion on implementation strategies. We estimated health effects (ie, disability-adjusted life-years averted) and resource implications for 2016-35, including patient-incurred costs. To assess resource requirements and cost-effectiveness, we compared scenarios with a base case representing continued current practice. FINDINGS: Incremental tuberculosis service costs differed by scenario and country, and in some cases they more than doubled existing funding needs. In general, expansion of tuberculosis services substantially reduced patient-incurred costs and, in India and China, produced net cost savings for most interventions under a societal perspective. In all three countries, expansion of access to care produced substantial health gains. Compared with current practice and conventional cost-effectiveness thresholds, most intervention approaches seemed highly cost-effective. INTERPRETATION: Expansion of tuberculosis services seems cost-effective for high-burden countries and could generate substantial health and economic benefits for patients, although substantial new funding would be required. Further work to determine the optimal intervention mix for each country is necessary. FUNDING: Bill & Melinda Gates Foundation.

Systematic review of mathematical models exploring the epidemiological impact of future TB vaccines.

Mathematical models are useful for assessing the potential epidemiological impact of future tuberculosis (TB) vaccines. We conducted a systematic review of mathematical models estimating the epidemiological impact of future human TB vaccines. PubMed, Embase and WHO Global Health Library were searched, 3-stage manual sifted, and citation- and reference-tracked, identifying 23 papers. An adapted quality assessment tool was developed, with a resulting median study quality score of 20/28. The literature remains divided as to whether vaccines effective pre- or post-infection would provide greatest epidemiological impact. However, all-age or adolescent/adult targeted prevention of disease vaccines achieve greater and more rapid impact than neonatal vaccines. Mass campaigns alongside routine neonatal vaccination can have profound additional impact. Economic evaluations found TB vaccines overwhelmingly cost-effective, particularly when targeted to adolescents/adults. The variability of impact by setting, age group and vaccine characteristics must be accounted for in the development and delivery of future TB vaccines.

Impact and cost-effectiveness of new tuberculosis vaccines in low- and middle-income countries.

To help reach the target of tuberculosis (TB) disease elimination by 2050, vaccine development needs to occur now. We estimated the impact and cost-effectiveness of potential TB vaccines in low- and middle-income countries using an age-structured transmission model. New vaccines were assumed to be available in 2024, to prevent active TB in all individuals, to have a 5-y to lifetime duration of protection, to have 40-80% efficacy, and to be targeted at "infants" or "adolescents/adults." Vaccine prices were tiered by income group (US $1.50-$10 per dose), and cost-effectiveness was assessed using incremental cost per disability adjusted life year (DALY) averted compared against gross national income per capita. Our results suggest that over 2024-2050, a vaccine targeted to adolescents/adults could have a greater impact than one targeted at infants. In low-income countries, a vaccine with a 10-y duration and 60% efficacy targeted at adolescents/adults could prevent 17 (95% range: 11-24) million TB cases by 2050 and could be considered cost-effective at $149 (cost saving to $387) per DALY averted. If targeted at infants, 0.89 (0.42-1.58) million TB cases could be prevented at $1,692 ($634-$4,603) per DALY averted. This profile targeted at adolescents/adults could be cost-effective at $4, $9, and $20 per dose in low-, lower-middle-, and upper-middle-income countries, respectively. Increased investments in adult-targeted TB vaccines may be warranted, even if only short duration and low efficacy vaccines are likely to be feasible, and trials among adults should be powered to detect low efficacies.